Allergic rhinitis (AR) is an IgE-mediated inflammation of the upper airway that causes naso-ocular congestion and pruritus, rhinorrhea, and sneezing. Colloquially referred to as hay fever, seasonal allergies, and allergies, AR is one of the most common chronic diseases, affecting 10-30% of adults and 40% of children. The genetics of AR have been understudied relative to those of asthma. We hypothesize that there are significant genetic determinants of AR, that these genes can be identified using integrative genomic approaches in at-risk populations, and that these genes interact in networks to regulate allergen-induced cytokine production in AR patients. We will test this hypothesis via three specific aims. First, we will perform a genome-wide analysis for single nucleotide polymorphisms (SNP) that alter risk for allergic rhinitis and replicate our findings in two independent cohorts. Second, we will pilot and implement a nasal epithelium collection protocol in asthmatic subjects, obtain gene expression profiles using this nasal epithelium resource, and perform integrative genomic analysis of allergic rhinitis using expression data from nasal epithelium and CD4+ lymphocytes. Third, we will perform luciferase reporter assays and measure allergen-induced cytokine proliferation to validate the biologic relevance of identified genetic variants, and model networks to integrate our experimental data within the context of immunologic pathways. We anticipate that functional variants identified from this proposal will elucidate immunologic pathways and define targets for disease prediction and therapeutic intervention. In addition to its scientific relevance, the proposed project outlines a career development plan that will train the principal investigator to become an independent investigator in the genetics and genomics of allergic disease.